Strategies to Stimulate Mobilization and Homing of Endogenous Stem and Progenitor Cells for Bone Tissue Repair

Abstract

The gold standard for the treatment of critical-size bone defects is autologous or allogenic bone graft. This has several limitations including donor site morbidity and the restricted supply of graft material. Cell-based tissue engineering strategies represent an alternative approach. Mesenchymal stem cells (MSCs) have been considered as a source of osteoprogenitor cells. More recently, focus has been placed on the use of endothelial progenitor cells (EPCs), since vascularization is a critical step in bone healing. Although many of these approaches have demonstrated effectiveness for bone regeneration, cell-based therapies require time consuming and cost-expensive in vitro cell expansion procedures. Accordingly, research is becoming increasingly focused on the homing and stimulation of native cells. The stromal cell-derived factor-1 (SDF-1) – CXCR4 axis has been shown to be critical for the recruitment of MSCs and EPCs. Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and has been targeted in many studies. Here, we present an overview of the different approaches for delivering homing factors to the defect site by absorption or incorporation to biomaterials, gene therapy, or via genetically manipulated cells. We further review strategies focusing on the stimulation of endogenous cells to support bone repair. Finally, we discuss the major challenges in the treatment of critical-size bone defects and fracture non-unions.

Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue‐engineered constructs via activating CXCR2‐Src‐PKL/Vav2‐Rac1

“…Recently, researchers have reviewed the studies using genetically modified cells to induce expression of homing factors, which in turn promote the recruitment of host EPCs (55). Viral transduction strategies are commonly performed to introduce specific gene sequences prior to cell implantation.…”

Engineering a Cell Home for Stem Cell Homing and Accommodation

“…Although the concept of endogenous regeneration has been validated in a variety of tissue systems and animal models, continued development of powerful tissue‐specific biomaterial devices based on a better understanding of the complex cellular pathways involved in cell trafficking across tissue development, growth and disease is needed to ensure sufficient cell homing and functional tissue regeneration in situ . Inspired by the natural compositions and structures of native tissue, great attention has been devoted to the development of biomaterials with extreme ECM‐mimicking properties.…”

“…In addition to immune considerations, this concept overcomes the difficulties and expense associated with cultivating, storing and distributing cells outside the human body. This strategy enables the human body to be used as a “bioreactor” to regenerate damaged tissue by applying a biomaterials‐based approach that does not require the delivery of ex vivo‐expanded cellular materials . A wide range of in vitro and in situ tissue engineering approaches have been pursued for more than three decades, and there have been remarkable discoveries and indisputable success stories from the laboratory to the patient .…”

Vascular precursor cells in tissue injury repair

“…The advantages of stimulating vascular precursor cell homing are the simplicity in application, inexpensive cost, and utilization of self-cell resources. VEGF, PDGF, SDF-1, and FGF have been tested in this application 269 . The direct absorption of vasculogenic mediators can achieve an immediate burst of stimulation, while continuing release from carrier materials entrapping vasculogenic factors, such as hydrogels, microspheres, and nanoparticles, allows generation of sustained and/or dynamic stimulations.…”